LIVE-AIR trial demonstrates efficacy of Lenzilumab for treatment of COVID patients with decreased oxygen saturation

The novel coronavirus 2019 (COVID-19) pandemic was caused by a new coronavirus, i.e., severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The RNA virus causes mild to severe symptoms and has a high transmission rate. In severe infection, patients often have a highly inflammatory response, which has been associated with morbidity and mortality due to COVID-19 disease. Therefore, researchers believe that early treatment of highly inflammatory responses can reduce the mortality rate. The phase 3 clinical trial of LIVE-AIR correlates with early treatment of severe inflammatory response with the humanized monoclonal antibody lenzilumab in hypoxic COVID-19 patients. The results of the study are published in medRxiv* Prepress server.

Study: The effect of baseline demographics and risk factors on survival with ventilation using a multivariate repeated logistic regression model.  Twelve covariates were included in the model that include known risk factors for progression to IMV and/or death by day 28: baseline CRP (CRP), disease severity at randomization (severity), respiratory status (asthma, COPD) , interstitial lung disease), age >= 65, diabetes (type 1 or type 2), lenzelumab (treated or placebo), body mass index, time from admission to randomization, time from symptoms to randomization, heart status ( High blood pressure, coronary artery disease, congestive heart failure), male gender, vascular condition (cerebral vascular disorders, thrombosis or embolism), other risk factors (pre-diagnosis of cancer; blood or non-blood disease), chronic kidney disease (including including kidney failure), or chronic liver disease (including hepatic failure).  Statistical significance was reached for all positions with a displayed probability value.. Image Credit: NIAID” class=”rounded-img” src=”https://d2jx2rerrg6sh3.cloudfront.net/images/news/ImageForNews_700872_1641445347383345.jpg” srcset=”https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/2000/src/images/news/ImageForNews_700872_1641445347383345.jpg 2000w, https://d2jx2rerrg6sh3.cloudfront.net/image-22010612ts/02 /ri/1950/src/images/news/ImageForNews_700872_1641445347383345.jpg 1950w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/1750/src/images/news/ImageForNews_70053872w3345.750 http://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/1550/src/images/news/ImageForNews_700872_1641445347383345.jpg 1550w, https://d2jx2rerrg6sh3.cloudfront.net/image/201061202/image-2201061202 ri/1350/src/images/news/ImageForNews_700872_1641445347383345.jpg 1350w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/1150/src/images/news/ImageForNews_https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/1150/src/images/news/ImageForNews_ https://d2jx2rerrg6sh3.164 //d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/950/src/images/news/ImageForNews_700872_1641445347383345.jpg 950w, https://  d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/750/src/images/news/ImageForNews_700872_1641445347383345.jpg 750w, https://d2jx2rerrg6sh3.cloudfront.net/image/22010655012ts/ /src/images/news/ImageForNews_700872_1641445347383345.jpg 550w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120226/ri/450/src/images/news/ImageForNews_700872_1641445347w” sizes=”(min-width: 1200px) 673px, (min-width: 1090px) 667px, (min-width: 992px) calc(66.6vw – 60px), (min-width: 480px) calc(100vw – 40px), calc(100vw) – 30px)” style=”width: 2000px;  height: 1281px;” width=”2000″ height=”1281″/><meta itemprop=Study: The effect of baseline demographics and risk factors on survival with ventilation using a multivariate repeated logistic regression model. Twelve covariates were included in the model that include known risk factors for progression to IMV and/or death by day 28: baseline CRP (CRP), disease severity at randomization (severity), respiratory status (asthma, COPD) , interstitial lung disease), age >= 65, diabetes (type 1 or type 2), lenzelumab (treated or placebo), body mass index, time from admission to randomization, time from symptoms to randomization, heart status ( High blood pressure, coronary artery disease, congestive heart failure), male gender, vascular condition (cerebral vascular disorders, thrombosis or embolism), other risk factors (pre-diagnosis of cancer; blood or non-blood disease), chronic kidney disease (including including kidney failure), or chronic liver disease (including hepatic failure). Statistical significance was reached for all positions with a displayed probability value.. Image Credit: NIAID

Highly inflammatory response and acute infection from COVID-19

The excessive inflammatory response is characterized by elevated secretion of post-inflammatory chemokines (MCP-1, IL-8, IP-10), cytokines (IL-6, IL-1), and myeloid cell activation and trafficking. The highly inflammatory response is also determined by assessment of levels of systemic inflammatory markers such as D-dimer and ferritin. Previous studies revealed that granulocyte-macrophage-colony stimulating factor (GM-CSF) is one of the early mediators associated with a hyper-inflammatory immune response, and thus an increased concentration of circulating GM-CSF is indicative of severe COVID-19 infection. Levels of C-reactive protein (CRP), which is driven by the increase of IL-6 after SARS-CoV-2 infection, are also directly related to disease severity.

The scientists noted that baseline CRP levels predict the requirements for oxygen supplementation in patients hospitalized with COVID-19 infection as well as exacerbation of organ failure. In the LIVE-AIR study, researchers found that participants who progressed to invasive mechanical ventilation (IMV) or died had CRP values ​​consistently above 100 mg/L during the hospital course. Studies have also shown that patients with CRP above 150 mg/L have aggressive hyper-inflammation associated with COVID-19 and are at risk of respiratory failure or death. Recently, researchers developed models using CRP for COVID-19 treatment guidelines. CRP can be used as a biomarker to understand the level of severity of COVID-19 disease. They hypothesized that early treatment of a hyperinflammatory immune response with lenzelumab might be possible by monitoring a patient’s C-reactive protein levels. Previous studies also suggested that CRP could be used as a biomarker to determine the extent of the highly inflammatory immune response in COVID-19 patients.

Lenzilumab and COVID-19 treatment

Lenzilumab is a neutralizing GM-CSF monoclonal antibody that has been evaluated to improve clinical outcomes in hospitalized hypoxic patients with COVID-19. In the Phase 3 LIVE-AIR clinical trial, lenzelumab was given to COVID-19 patients with low oxygen saturation (SpO)2≤94%) in room air or in patients who required supplemental oxygen but did not need IMV within 2 days after hospitalization. Another group of patients was treated with a placebo infusion along with standard treatments including corticosteroids and remdesivir.

Effect of baseline demographics and risk factors on survival with ventilation using a multivariate repeated logistic regression model.  Twelve covariates were included in the model that include known risk factors for progression to IMV and/or death by day 28: baseline CRP (CRP), disease severity at randomization (severity), respiratory status (asthma, COPD) , interstitial lung disease), age >= 65, diabetes (type 1 or type 2), lenzelumab (treated or placebo), body mass index, time from admission to randomization, time from symptoms to randomization, heart status ( High blood pressure, coronary artery disease, congestive heart failure), male gender, vascular condition (cerebral vascular disorders, thrombosis or embolism), other risk factors (pre-diagnosis of cancer; blood or non-blood disease), chronic kidney disease (including including kidney failure), or chronic liver disease (including hepatic failure).  Statistical significance was reached for all parameters with the presented probability value.” class=”rounded-img” src=”https://d2jx2rerrg6sh3.cloudfront.net/images/news/ImageForNews_700872_16414452827738369.jpg” srcset=”https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120124/ri/1280/src/images/news/ImageForNews_700872_16414452827738369.jpg 1280w, https://d2jx2rerrg6sh3.cloudfront.net//2022010handler/image-handler/ /ri/1250/src/images/news/ImageForNews_700872_16414452827738369.jpg 1250w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120124/ri/1050/src/images/news/ImageForNews_1445282750_16469_700872_732 http://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120124/ri/850/src/images/news/ImageForNews_700872_16414452827738369.jpg 850w, https://d2jx2rerrg6sh3.cloudfront.net//202-2010612012 ri/650/src/images/news/ImageForNews_700872_16414452827738369.jpg 650w, https://d2jx2rerrg6sh3.cloudfront.net/image-handler/ts/20220106120124/ri/450/src/images/news/ImageForNews_70045872w16469_700″ sizes=”(min-width: 1200px) 673px, (min-width: 1090px) 667px, (min-width: 992px) calc(66.6vw – 60px), (min-width: 480px) calc(100vw – 40px), calc(100vw) – 30px)” style=”width: 1280px;  height: 731px;” width=”1280″ height=”731″/></p>
<p style=Effect of baseline demographics and risk factors on survival with ventilation using a multivariate repeated logistic regression model. Twelve covariates were included in the model that include known risk factors for progression to IMV and/or death by day 28: baseline CRP (CRP), disease severity at randomization (severity), respiratory status (asthma, COPD) , interstitial lung disease), age >= 65, diabetes (type 1 or type 2), lenzelumab (treated or placebo), body mass index, time from admission to randomization, time from symptoms to randomization, heart status ( High blood pressure, coronary artery disease, congestive heart failure), male gender, vascular condition (cerebral vascular disorders, thrombosis or embolism), other risk factors (pre-diagnosis of cancer; blood or non-blood disease), chronic kidney disease (including including kidney failure), or chronic liver disease (including hepatic failure). Statistical significance was reached for all parameters with the presented probability value.

In this phase III, double-blind, placebo-controlled trial, 520 participants were randomized and stratified according to age and disease severity to receive lenzelumab or placebo on day 0. The study group was controlled for twenty-eight days. The scientists reported that lenzelumab treatment significantly enhanced survival without invasive mechanical ventilation (SWOV) compared to a placebo-treated control group. Significant improvement has been reported in patients with baseline CRP <150 mg/L. The scientists observed that lenzelumab reduced C-reactive protein levels in patients more quickly than a placebo. CRP levels were more predictive of SWOV. This study also showed that lenzelumab was well tolerated without causing any adverse effects in the study group.

A recent study showed that tocilizumab (an IL-6 receptor blocker) treatment significantly improved the outcome of severely affected COVID-19 patients with a mean CRP of 143 mg/L. Although tocilizumab treatment reduced ICU admission or mortality among patients with baseline CRP >150 mg/L, it was not effective for patients with baseline CRP of 150 mg/L. In addition, COVID-19 patients with CRP≥200mg/L were treated with systemic glucocorticoids within 48 hours of hospital admission, but if CRP was less than or equal to 99 mg/L, systemic corticosteroid use could be harmful. Therefore, the scientists suggested that blocking GM-CSF signaling after monitoring the level of CRP could be a useful therapeutic approach to prevent progression to severe disease.

conclusion

Scientists have determined that CRP levels can guide treatment of early inflammatory response with lenzelumab, which significantly reduces IMV and death from COVID-19 infection. They noted that the GM-CSF increase may occur as a patient progresses toward severe disease. The scientists reported that GM-CSF neutralization with lenzilumab significantly improved SWOV in the study group. In the future, the results of this study will be validated by the ACTIV-5/BET-B trial sponsored by the National Institutes of Health.

*Important note

medRxiv It publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behaviour, or be treated as established information.

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